WO2023057423A1 - Dérivés de cyclohepta-thièno-diazépine utilisés en tant que modulateurs allostériques positifs du récepteur gaba a gamma1 - Google Patents

Dérivés de cyclohepta-thièno-diazépine utilisés en tant que modulateurs allostériques positifs du récepteur gaba a gamma1 Download PDF

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WO2023057423A1
WO2023057423A1 PCT/EP2022/077524 EP2022077524W WO2023057423A1 WO 2023057423 A1 WO2023057423 A1 WO 2023057423A1 EP 2022077524 W EP2022077524 W EP 2022077524W WO 2023057423 A1 WO2023057423 A1 WO 2023057423A1
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Prior art keywords
thia
difluorophenyl
methyl
octadeca
tetrazatetracyclo
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PCT/EP2022/077524
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English (en)
Inventor
Bjoern Bartels
Giuseppe Cecere
Guido Galley
Luca Gobbi
Martin Goebel
Maria-Clemencia Hernandez
Andrés Miguel OLIVARES MORALES
Hasane Ratni
Michael REUTLINGER
Valerie Runtz-Schmitt
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F. Hoffmann-La Roche Ag
Hoffmann-La Roche Inc.
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Application filed by F. Hoffmann-La Roche Ag, Hoffmann-La Roche Inc. filed Critical F. Hoffmann-La Roche Ag
Priority to CN202280064368.7A priority Critical patent/CN118019745A/zh
Publication of WO2023057423A1 publication Critical patent/WO2023057423A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D495/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings

Definitions

  • the present invention relates to organic compounds useful for therapy or prophylaxis in a mammal, and in particular to new cyclohepta-thieno-diazepine derivatives that exhibit activity as GABAA ⁇ 1 receptor positive allosteric modulators (PAMs) and are thus useful for the treatment or prophylaxis of GABAA ⁇ 1 receptor related diseases or conditions.
  • PAMs GABAA ⁇ 1 receptor positive allosteric modulators
  • GABA gamma-aminobutyric acid
  • GABA A receptors which are members of the ligand- gated ion channel superfamily
  • GABA B receptors which are members of the G- protein linked receptor family.
  • the GABA A receptor complex which is a membrane-bound heteropentameric protein polymer is composed principally of ⁇ , ⁇ and ⁇ subunits.
  • GABAA receptors are ligand-gated chloride channels and the principal mediators of inhibitory neurotransmission in the human brain.
  • GABAA receptor subunits There are 19 genes encoding for GABAA receptor subunits that assemble as pentamers with the most common stoichiometry being two ⁇ , two ⁇ and one ⁇ subunit. GABA A subunit combinations give rise to functional, circuit, and behavioral specificity. GABAA receptors containing the ⁇ 1 subunit (GABAA ⁇ 1) are of particular interest due to their enriched expression in the limbic system and unique physiological and pharmacological properties.
  • the GABA A ⁇ 1 subunit-containing receptors while less abundant (around 5-10 % of total expression of GABAA receptors in the brain) than ⁇ 2 subunit-containing receptors exhibit an enriched brain mRNA and protein distribution in key brain areas such as extended amygdala (central, medial, and bed nucleus of the stria terminalis), lateral septum, hypothalamus, and pallidum/nigra. These structures form the interconnected core of a subcortical limbic circuit regulating motivated social and affective behaviors. In CNE, 18.08.2022 abnormal or disease conditions, hyper-recruitment of this circuit promotes anxiety, arousal, aggression, fear and defense while inhibiting foraging and social interactions.
  • a GABAA yl positive allosteric modulator may be an effective treatment as a symptomatic or disease- modifying agent.
  • a CNS disorders of particular interest in the context of the present invention is autism spectrum disorder (ASD), including its core symptoms and associated comorbidities, such as anxiety and irritability, social anxiety disorder (social phobia) and generalized anxiety disorder.
  • ASD is a complex, heterogeneous neurodevelopmental disorder characterized by impairments in two core domains: impairments in social interaction and communication, and presence of repetitive or restricted behaviors, interests, or activities (American Psychiatric Association 2013).
  • GABRG1 GABAA yl
  • Mutations in 4pl2 gene cluster have been linked to increased risk of anxiety, substance abuse and eating disorders - providing a link between GABRGl/4pl2 and affective dysfunction.
  • MRS studies found altered GABA levels in ASD and in particular some recent studies showed reduced GABA and altered somatosensory function in children with ASD and.
  • a reduced number of inhibitory interneurons were found from postmortem tissues of ASD and TS patients.
  • reduced GABA synthesizing enzymes, glutamic acid decarboxylase (GAD) 65 and 67 were found in parietal and cerebellar cortices of patients with autism.
  • Compounds of the present invention are selective GABAA yl receptor positive allosteric modulators (PAMs) that selectively enhance the function of yl -containing GABAA receptors by increasing GABAergic currents (influx of chloride) at a given concentration (e.g. EC20) of gamma amino butyric acid (GABA).
  • PAMs GABAergic currents
  • GABA gamma amino butyric acid
  • the compounds of the present invention have high PAM efficacy and binding selectivity for the yl -containing subtypes ( ⁇ 5yl, ⁇ 2yl, ⁇ lyl) relative to the y2-containing subtypes (e.g. ⁇ 1 2, ⁇ 2y2, ⁇ 3y2 and ⁇ 5y2).
  • compounds of the present invention are strongly differentiated from classical benzodiazepine drugs such as Alprazolam, Triazolam, Estazolam, and Midazolam, which are selective for the y2-containing GABAA subtypes and possess low affinity for the yl- containing subtypes.
  • selective GABAA yl PAMs will restore GABAergic signaling in key brain regions (e.g. extended amygdala: central, medial, and bed nucleus of the stria terminalis, lateral septum, hypothalamus, and pallidum/nigra) without the side-effects of non-selective GABAA modulators (e.g. benzodiazepines).
  • the selective GABAA yl PAMs described herein and their pharmaceutically acceptable salts and esters are useful, alone or in combination with other drugs, as disease-modifying or as symptomatic agents for the treatment or prevention of acute neurological disorders, chronic neurological disorders and/or cognitive disorders, including autism spectrum disorders (ASD), Angelman syndrome, age-related cognitive decline, Rett syndrome, Prader-Willi syndrome, amyotrophic lateral sclerosis (ALS), fragile-X disorder, negative and/or cognitive symptoms associated with schizophrenia, tardive dyskinesia, anxiety, social anxiety disorder (social phobia), panic disorder, agoraphobia, generalized anxiety disorder, disruptive, impulse-control and conduct disorders, Tourette’s syndrome (TS), obsessive-compulsive disorder (OCD), acute stress disorder, post-traumatic stress disorder (PTSD), attention deficit hyperactivity disorder (ADHD), sleep disorders, Parkinson’s disease (PD), Huntington’s chorea, Alzheimer’s disease (AD), mild cognitive impairment (MCI), dementia, behavioral and psychological symptoms (BPS) in
  • the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.
  • the present invention provides a process of manufacturing the compounds of formula (I) described herein, wherein said process is as described in any one of Schemes 1 to 15 herein.
  • the present invention provides a compound of formula (I) as described herein, when manufactured according to the processes described herein. In a further aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use as therapeutically active substance.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use in a method for treating or preventing acute neurological disorders, chronic neurological disorders and/or cognitive disorders in a subject.
  • a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use in a method for treating or preventing acute neurological disorders, chronic neurological disorders and/or cognitive disorders in a subject.
  • Detailed Description of the Invention Definitions Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein, unless incompatible therewith. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and/or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and/or steps are mutually exclusive.
  • alkyl refers to a mono- or multivalent, e.g., a mono- or bivalent, linear or branched saturated hydrocarbon group of 1 to 6 carbon atoms (“C1-C6-alkyl”), e.g., 1, 2, 3, 4, 5, or 6 carbon atoms.
  • the alkyl group contains 1 to 3 carbon atoms, e.g., 1, 2 or 3 carbon atoms.
  • alkyl examples include methyl, ethyl, propyl, 2-propyl (isopropyl), n-butyl, iso-butyl, sec-butyl, tert-butyl, and 2,2- dimethylpropyl. Particularly preferred, yet non-limiting examples of alkyl include methyl and ethyl.
  • alkoxy refers to an alkyl group, as previously defined, attached to the parent molecular moiety via an oxygen atom. Unless otherwise specified, the alkoxy group contains 1 to 6 carbon atoms (“C 1 -C 6 -alkoxy”). In some preferred embodiments, the alkoxy group contains contains 1 to 4 carbon atoms.
  • the alkoxy group contains 1 to 3 carbon atoms.
  • Some non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy. Particularly preferred, yet non-limiting examples of alkoxy are ethoxy and tert-butoxy.
  • the term “halogen” or “halo” refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I).
  • the term “halogen” or “halo” refers to fluoro (F), chloro (Cl) or bromo (Br).
  • halogen or “halo” are fluoro (F) and chloro (Cl).
  • cycloalkyl refers to a saturated or partly unsaturated monocyclic or bicyclic hydrocarbon group of 3 to 10 ring carbon atoms (“C3-C10-cycloalkyl”). In some preferred embodiments, the cycloalkyl group is a saturated monocyclic hydrocarbon group of 3 to 8 ring carbon atoms.
  • “Bicyclic cycloalkyl” refers to cycloalkyl moieties consisting of two saturated carbocycles having two carbon atoms in common, i.e., the bridge separating the two rings is either a single bond or a chain of one or two ring atoms, and to spirocyclic moieties, i.e., the two rings are connected via one common ring atom.
  • the cycloalkyl group is a saturated monocyclic hydrocarbon group of 3 to 6 ring carbon atoms, e.g., of 3, 4, 5 or 6 carbon atoms.
  • cycloalkyl examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and spiro[2.3]hexan-5-yl.
  • heterocyclyl or “heterocycloalkyl” refers to a saturated or partly unsaturated mono- or bicyclic, preferably monocyclic ring system of 3 to 14 ring atoms, preferably 3 to 10 ring atoms, more preferably 3 to 8 ring atoms, most preferably 3 to 6 ring atoms, wherein 1, 2, or 3 of said ring atoms are heteroatoms selected from N, O and S, the remaining ring atoms being carbon.
  • 1 to 2 of said ring atoms are selected from N and O, the remaining ring atoms being carbon.
  • Bicyclic heterocyclyl refers to heterocyclic moieties consisting of two cycles having two ring atoms in common, i.e., the bridge separating the two rings is either a single bond or a chain of one or two ring atoms, and to spirocyclic moieties, i.e., the two rings are connected via one common ring atom.
  • heterocyclyl groups include azetidin-3-yl; azetidin-2-yl; oxetan-3-yl; oxetan-2-yl; piperidyl; piperazinyl; pyrrolidinyl; 2-oxopyrrolidin-1-yl; 2- oxopyrrolidin-3-yl; 5-oxopyrrolidin-2-yl; 5-oxopyrrolidin-3-yl; 2-oxo-1-piperidyl; 2-oxo- 3-piperidyl; 2-oxo-4-piperidyl; 6-oxo-2-piperidyl; 6-oxo-3-piperidyl; 1-piperidinyl; 2- piperidinyl; 3-piperidinyl; 4-piperidinyl; morpholino (e.g., morpholin-2-yl or morpholin-3- yl); thiomorpholino, pyrrolidinyl (e.
  • heterocyclyl is azetidine.
  • heteroaryl refers to a mono- or multivalent, monocyclic or bicyclic, preferably bicyclic ring system having a total of 5 to 14 ring members, preferably, 5 to 12 ring members, and more preferably 5 to 10 ring members, wherein at least one ring in the system is aromatic, and at least one ring in the system contains one or more heteroatoms.
  • heteroaryl refers to a 5-10 membered heteroaryl comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N.
  • heteroaryl refers to a 5-10 membered heteroaryl comprising 1 to 2 heteroatoms independently selected from O and N.
  • heteroaryl include 2-pyridyl, 3-pyridyl, 4- pyridyl, pyridazinyl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrimidin-6-yl, indol- 1-yl, 1H-indol-2-yl, 1H-indol-3-yl, 1H-indol-4-yl, 1H-indol-5-yl, 1H-indol-6-yl, 1H-indol- 7-yl, 1,2-benzoxazol-3-yl, 1,2-benzoxazol-4-yl, 1,2-benzoxazol-5-yl, 1,2-benzoxazol-6-yl, 1,2-benzoxazol-7-
  • heteroaryl refers to pyridazinyl.
  • hydroxy refers to an –OH group.
  • haloalkyl refers to an alkyl group, wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a halogen atom, preferably fluoro.
  • haloalkyl refers to an alkyl group wherein 1, 2 or 3 hydrogen atoms of the alkyl group have been replaced by a halogen atom, most preferably fluoro.
  • Non-limiting examples of haloalkyl are fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, 2-fluoroethyl, and 2,2-difluoroethyl. Particularly preferred, yet non-limiting examples of haloalkyl are difluoromethyl, trifluoromethyl, and 2-fluoroethyl.
  • the term “hydroxyalkyl” refers to an alkyl group, wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a hydroxy group.
  • hydroxyalkyl refers to an alkyl group wherein 1, 2 or 3 hydrogen atoms, most preferably 1 hydrogen atom of the alkyl group have been replaced by a hydroxy group.
  • hydroxyalkyl are hydroxymethyl, hydroxyethyl (e.g.2- hydroxyethyl), 2-hydroxy-2-methyl-propyl, and 3-hydroxy-3-methyl-butyl.
  • hydroxycycloalkyl refers to an cycloalkyl group, wherein at least one of the hydrogen atoms of the cycloalkyl group has been replaced by a hydroxy group.
  • hydroxycycloalkyl refers to a cycloalkyl group wherein 1, 2 or 3 hydrogen atoms, most preferably 1 hydrogen atom of the cycloalkyl group have been replaced by a hydroxy group.
  • hydroxyalkyl are hydroxcyclobutyl (e.g., 3- hydroxycyclobutyl) and hydroxycyclopropyl (e.g., 1 -hydroxy cyclopropyl).
  • halohydroxyalkyl refers to an alkyl group, wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a hydroxy group and at least one of the hydrogen atoms of the alkyl group has been replaced by a halogen atom.
  • halohydroxyalkyl refers to an alkyl group wherein 1, 2 or 3 hydrogen atoms, most preferably 1 hydrogen atom of the alkyl group have been replaced by a hydroxy group and 1, 2 or 3 hydrogen atoms, most preferably 3 hydrogen atoms of the alkyl group have been replaced by a halogen atom.
  • a preferred, yet non-limiting example of halohydroxyalkyl is 3,3,3 -trifluoro-2-hydroxy-2-methyl-propyl.
  • salts refers to those salts which retain the biological effectiveness and properties of the free bases or free acids, which are not biologically or otherwise undesirable.
  • the salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, in particular hydrochloric acid, and organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, lactic acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcy stein and the like.
  • salts derived from an inorganic base include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium salts and the like.
  • Salts derived from organic bases include, but are not limited to salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyimine resins and the like.
  • Particular pharmaceutically acceptable salts of compounds of formula (I) are hydrochlorides, fumarates, formates, lactates (in particular derived from L-(+)-lactic acid), tartrates (in particular derived from L-(+)-tartaric acid) and trifluoroacetates.
  • the compounds of formula (I) can contain several asymmetric centers and can be present in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereioisomers, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates.
  • the asymmetric carbon atom can be of the "R” or "S” configuration.
  • treatment includes: (1) inhibiting the state, disorder or condition (e.g. arresting, reducing or delaying the development of the disease, or a relapse thereof in case of maintenance treatment, of at least one clinical or subclinical symptom thereof); and/or (2) relieving the condition (i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms).
  • the benefit to a patient to be treated is either statistically significant or at least perceptible to the patient or to the physician.
  • a medicament is administered to a patient to treat a disease, the outcome may not always be effective treatment.
  • prophylaxis or “prevention” as used herein includes: preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a subject and especially a human that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition.
  • subject includes both humans and non-humans and includes but is not limited to humans, non-human primates, canines, felines, murines, bovines, equines, and porcines. In a particularly preferred embodiment, the term “subject” refers to humans.
  • uM means microMolar and is equivalent to the symbol ⁇ M.
  • the abbreviation uL means microliter and is equivalent to the symbol ⁇ L.
  • the abbreviation ug means microgram and is equivalent to the symbol ⁇ g.
  • the present invention provides a compound of formula (I)
  • R 1 is selected from hydrogen, C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, R 1a R 1b NC(O)-, C 3 - C10-cycloalkyl, 3-14-membered heteroaryl;
  • R 1a is selected from C1-C6-alkyl, hydroxy-C1-C6-alkyl, halo-C1-C6-alkyl, halo- hydroxy-C 1 -C 6 -alkyl, C 3 -C 10 -cycloalkyl, hydroxy-C 3 -C 10 -cycloalkyl-C 1 -C 6 - alkyl-;
  • R 1b is hydrogen; or R 1a and R 1b , taken together with the nitrogen atom to which they are attached, form a 3-14-membered heterocycle which is optionally substituted with one substituent selected from halogen, hydroxy, and C 1
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein is selected from: R 1 is selected from C 1 -C 6 -alkyl and R 1a R 1b NC(O)-; R 1a is selected from hydroxy-C1-C6-alkyl and halo-hydroxy-C1-C6-alkyl; and R 1b is hydrogen.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein is selected from: R 1 is selected from methyl and R 1a R 1b NC(O)-; R 1a is selected from 2-hydroxy-2-methyl-propyl and 3,3,3-trifluoro-2-hydroxy-2- methyl-propyl; and R 1b is hydrogen.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein is selected from: ; wherein R 1 is as described herein.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein is ; wherein R 1 is as described herein. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein
  • R 1 is as described herein.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein is wherein R 1 is as described herein.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein is wherein R 1 is as described herein. In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein is ; wherein R 1 is as described herein.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: R 1 is selected from C 1 -C 6 -alkyl and R 1a R 1b NC(O)-; R 1a is selected from hydroxy-C1-C6-alkyl and halo-hydroxy-C1-C6-alkyl; and R 1b is hydrogen.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from methyl and R 1a R 1b NC(O)-; R 1a is selected from 2-hydroxy-2-methyl-propyl and 3,3,3-trifluoro-2-hydroxy-2- methyl-propyl; and R 1b is hydrogen.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 1 is R 1a R 1b NC(O)-; R 1a is selected from 2-hydroxy-2-methyl-propyl; and R 1b is hydrogen.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 2 is C1-C6-alkyl. In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 2 is methyl. In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 3 is fluoro.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: Y 1 , Y 3 , Y 4 , and Y 5 are each independently selected from O and CR 4 R 5 , provided that at most two of Y 1 , Y 3 , Y 4 , and Y 5 are O and that an Y being O is not bound to another Y also being O; Y 2 is CR 4 R 5 ; R 4 is selected from hydrogen, deuterium, halogen, and hydroxy; and R 5 is selected from hydrogen, deuterium, and halogen.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: Y 1 and Y 4 are each independently selected from O and CR 4 R 5 ; Y 2 , Y 3 , and Y 5 are each CR 4 R 5 ; R 4 is selected from hydrogen and halogen; and R 5 is hydrogen.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: Y 1 and Y 4 are each independently selected from O and CR 4 R 5 ; Y 2 , Y 3 , and Y 5 are each CR 4 R 5 ; R 4 is selected from hydrogen and fluoro; and R 5 is hydrogen.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: Y 1 is selected from CH2, CH-F, CH-OH, and O; Y 2 is selected from CH 2 , CD 2 , CH-Me, CH-F, CF 2 , and CH-OH; Y 3 is selected from CH2, CD2, CH-F, CH-OH, and O; and Y 4 and Y 5 are each independently selected from CH2 and O; provided that at most two of Y 1 , Y 3 , Y 4 , and Y 5 are O and that an Y being O is not bound to another Y also being O.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: Y 1 and Y 4 are each independently selected from CH 2 and O; Y 2 is selected from CH2 and CH-F; and Y 3 and Y 5 are both CH2.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: Y 1 and Y 4 are both O; and Y 2 , Y 3 , and Y 5 are all CH 2 .
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: is selected from: R 1 is selected from C1-C6-alkyl and R 1a R 1b NC(O)-; R 1a is selected from hydroxy-C1-C6-alkyl and halo-hydroxy-C1-C6-alkyl; R 1b is hydrogen; R 2 is C 1 -C 6 -alkyl; R 3 is fluoro; Y 1 and Y 4 are each independently selected from O and CR 4 R 5 ; Y 2 , Y 3 , and Y 5 are each CR 4 R 5 ; R 4 is selected from hydrogen and halogen; and R 5 is hydrogen.
  • R 1 is selected from C1-C6-alkyl and R 1a R 1b NC(O)-
  • R 1a is selected from hydroxy-C1-C6-alkyl and halo-hydroxy-C1-C6-alkyl
  • R 1b is
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: is selected from: R 1 is selected from methyl and R 1a R 1b NC(O)-; R 1a is selected from 2-hydroxy-2-methyl-propyl and 3,3,3-trifluoro-2-hydroxy-2- methyl-propyl; R 1b is hydrogen; R 2 is methyl; R 3 is fluoro; Y 1 and Y 4 are each independently selected from O and CR 4 R 5 ; Y 2 , Y 3 , and Y 5 are each CR 4 R 5 ; R 4 is selected from hydrogen and fluoro; and R 5 is hydrogen.
  • R 1 is selected from methyl and R 1a R 1b NC(O)-
  • R 1a is selected from 2-hydroxy-2-methyl-propyl and 3,3,3-trifluoro-2-hydroxy-2- methyl-propyl
  • R 1b is hydrogen
  • R 2 is methyl
  • R 3 is fluoro
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is selected from: 9-(2,6-difluorophenyl)-3-methyl-18-thia-2,4,5,8- tetrazatetracyclo[8.8.0.02,6.011,17]octadeca-1(10),3,5,8,11(17)-pentaene; (7S)-9-(2,6-difluorophenyl)-3,7-dimethyl-18-thia-2,4,5,8- tetrazatetracyclo[8.8.0.02,6.011,17]octadeca-1(10),3,5,8,11(17)-pentaene; (7S)-3-cyclopropyl-9-(2,6-difluorophenyl)-7-methyl-18-thia-2,4,5,8- tetrazatetracyclo[8.8.0.02,6.011,17]
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is selected from: (7S, 15S)-9-(2,6-difhiorophenyl)-15-fluoro-3,7-dimethyl-18-thia-2,4,5,8- tetrazatetracyclo[8.8.0.02,6.011,17]octadeca-l(10),3,5,8, l l(17)-pentaene;
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is (75)-9-(2,6-difhrorophenyl)-7V-(2-hydroxy-2-methyl-propyl)-7-methyl- 13, 16-dioxa- 18- thia-2, 5 , 8 -triazatetracyclo [8.8.0.02, 6.011, 17]octadeca- 1(10), 3, 5, 8, 11(17)-pentaene-4- carboxamide.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is (7S, 15S)-9-(2,6-dmuorophenyl)-15-fluoro-3,7-dimethyl-18-thia-2,4,5,8- tetrazatetracyclo[8.8.0.02,6.011,17]octadeca-l(10),3,5,8, l l(17)-pentaene.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is (7S)-9-(2,6-difhrorophenyl)-N-(2-hydroxy-2-methyl-propyl)-7-methyl-13,16-dioxa-18- thia-2,3,5,8-tetrazatetracyclo[8.8.0.02,6.011,17]octadeca-l(10),3,5,8,l l(17)-pentaene-4- carboxamide.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is (7S)-9-(2,6-difluorophenyl)-7-methyl-N-[(2R)-3,3,3-trifluoro-2-hydroxy-2-methyl- propyl]-13, 16-dioxa-18-thia-2,3,5,8-tetrazatetracyclo[8.8.0.02,6.011,17]octadeca- 1(10), 3, 5, 8, 11(17)-pentaene-4-carboxamide.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is (7S)-9-(2,6-difluorophenyl)-7-methyl-N-[(2S)-3,3,3-trifluoro-2-hydroxy-2-methyl- propyl]-13, 16-dioxa-18-thia-2,3,5,8-tetrazatetracyclo[8.8.0.02,6.011,17]octadeca- 1(10), 3, 5, 8, 11(17)-pentaene-4-carboxamide.
  • the present invention provides pharmaceutically acceptable salts of the compounds of formula (I) as described herein, especially pharmaceutically acceptable salts selected from hydrochlorides, fumarates, lactates (in particular derived from L-(+)- lactic acid), tartrates (in particular derived from L-(+)-tartaric acid) and trifluoroacetates.
  • the present invention provides compounds according to formula (I) as described herein (i.e., as “free bases” or “free acids”, respectively).
  • the compounds of formula (I) are isotopically-labeled by having one or more atoms therein replaced by an atom having a different atomic mass or mass number.
  • isotopically-labeled (i.e., radiolabeled) compounds of formula (I) are considered to be within the scope of this disclosure.
  • isotopes that can be incorporated into the compounds of formula (I) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine, and iodine, such as, but not limited to, 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 C1, 123 I, and 125 I, respectively.
  • Certain isotopically-labeled compounds of formula (I) for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium, i.e.
  • a compound of formula (I) can be enriched with 1, 2, 5, 10, 25, 50, 75, 90, 95, or 99 percent of a given isotope.
  • substitution with heavier isotopes such as deuterium, i.e. 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements.
  • Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the Examples as set out below using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.
  • the preparation of compounds of formula (I) of the present invention may be carried out in sequential or convergent synthetic routes. Syntheses of the compounds of the invention are shown in the following schemes. The skills required for carrying out the reactions and purifications of the resulting products are known to those skilled in the art. The substituents and indices used in the following description of the processes have the significance given herein before and in the claims, unless indicated to the contrary.
  • the compounds of formula (I) can be manufactured by the methods given below, by the methods given in the examples or by analogous methods. Appropriate reaction conditions for the individual reaction steps are known to a person skilled in the art.
  • the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents. However, a period of from 0.5 h to several days will usually suffice to yield the described intermediates and compounds.
  • the reaction sequence is not limited to the one displayed in the schemes, however, depending on the starting materials and their respective reactivity the sequence of reaction steps can be freely altered. Starting materials are either commercially available or can be prepared by methods analogous to the methods given below, by methods described in references cited in the description or in the examples, or by methods known in the art.
  • the compounds of formula (I) can be manufactured by the methods given below, by the methods given in the examples or by analogous methods. Appropriate reaction conditions for the individual reaction steps are known to a person skilled in the art.
  • the reaction sequence is not limited to the one displayed in schemes 1 - 15, however, depending on the starting materials and their respective reactivity the sequence of reaction steps can be freely altered.
  • Starting materials are either commercially available or can be prepared by methods analogous to the methods given below, by methods described in references cited in the description or in the examples, or by methods known in the art.
  • the present compounds of formula (I) and their pharmaceutically acceptable salts may be prepared by a process described below (Schemes 1 to 15).
  • a compound of formula (la) can be prepared from lactames of formula (II). Following thionation reaction using Lawesson’s reagent or P2S5, lactames (II) are converted to corresponding thiolactames (III). Their reaction with hydrazides (IV) via a Pellizzari type process yields 1,2,4-triazoles of general formula (la). In alternative, 1,2,4- triazoles (la) can be obtained by reaction between thiolactames (II) and hydrazine to form hydrazones (V) followed by treatment with the corresponding trialkyl orthoacetate or acid chloride (VI).
  • lactams (II) can be directly converted into 1,2,4-triazoles of formula (la) by treatment with bis(2-oxo-3-oxazolidinyl)phosphinic chloride, followed by reaction with hydrazides (IV) in presence of a strong base such as sodium hydride.
  • compounds of formula (lb) can be prepared from lactams (II) by the process described below (Scheme 2). Electrophilic amination of lactams (II) using a suitable reagent such as O-(diphenylphosphinyl)hydroxylamine yields intermediates of formula (VII). Their final thermal cyclocondensation reaction with imidates (VIII) provides 1,2,4-triazoles (lb).
  • esters (IX) are reacted with an amine (X) with or without addition of a suitable catalyst such as isopropylmagnesium chloride to form 1,2,4- triazole amides of formula (lb).
  • esters (IX) can be saponified to the corresponding acids (XI) under basic conditions, for instance by treatment with an aqueous or alcoholic solution of sodium hydroxide or lithium hydroxide.
  • 1,2,4-triazole amides (lb) are obtained by standard amide coupling reaction between acids (XI) and amines HNR 4 R 5 (X).
  • imidazoles of formula (Id) can be prepared as described below (Scheme 5).
  • Thiolactams (III) are reacted with ammonia to form amidines of formula (XII).
  • amidines (XII) can be converted to methyl imidazoles (Id).
  • imidazoles of formula (le) can be prepared as described below (Scheme 6). Lactams (II) are reacted with amino alcohols (XIII) following activation with bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-CI) in presence of a base (NaH). Primary alcohols (XIV) are then cyclized under oxidative conditions to provide imidazoles of formula (le).
  • compounds of formula (If) can be prepared as described below (Scheme 7).
  • Amidines (XII) are reacted with ethyl propiolate to form pyrimido[l,2-a][l,4]benzodiazepin-3-ones (XV).
  • a brominating agent such as V-bromosuccinimide (NBS) and subsequent Suzuki-reaction with trimethylboroxine, compounds of formula (If) can be obtained.
  • geminal difluorinated derivatives of formula (I) and monofluorinated derivatives of formula (I) can be prepared as described below (Scheme 9).
  • Dioxolanes (XVIII) are deprotected by exposure to acids such as acetic acid to provide ketones (XIX). Their reduction with lithium or potassium borohydride affords secondary alcohols (XX).
  • a fluorinating agent such as diaminosulfur trifluoride (DAST) or Deoxo-Fluor® affords geminal difluorinated derivatives (I) or monofluorinated derivatives (I), respectively.
  • Resulting diastereomers can be separated by chromatography.
  • germinal difluorinated derivatives of formula (I) and monofluorinated derivatives of formula (I) can be prepared as described below (Scheme 10).
  • Dioxolanes (XXI) are deprotected by exposure to acids such as acetic acid to provide ketones (XXII). Their reduction with lithium or potassium borohydride affords secondary alcohols (XXIII).
  • a fluorinating agent such as diaminosulfur trifluoride (DAST) or Deoxo-Fluor® affords geminal difluorinated derivatives (I) or monofluorinated derivatives (I), respectively.
  • Resulting diastereomers can be separated by chromatography.
  • vicinal difluorinated derivatives of formula (I) can be prepared as described below (Scheme 11). Alkenes (XXIV) are treated with a mixture of V-bromosuccinimide and Olah’s reagent (py HF), followed by silver(I) fluoride (AgF) to give vicinal difluorinated derivatives (I) as a mixture of diastereomers, that can be separated by chromatography.
  • the required regioisomer can be obtained pure after chromatographic removal of the undesired minor isomer and this can be performed at any stage of the synthesis.
  • Compounds of formula (XXX) can be prepared by an amide coupling reaction between 2-amino-thiophenes (XXIX) and A-Boc or V-Cbz protected Z-amino acids upon activation with phosphoryl chloride (POCI3), or by other methods known to those skilled in the art. Removal of A-Boc or N-Cbz protecting group can be effected with mineral acids (e.g. HC1) or organic acids (e.g. trifluoroacetic acid) to yield amines of formula (XXXI).
  • mineral acids e.g. HC1
  • organic acids e.g. trifluoroacetic acid
  • V-Cbz protected intermediates XXX
  • the deprotection reaction can be accomplished in addition by hydrogenation or using iodotrimethylsilane.
  • Final intramolecular condensation reaction promoted by acidic media e.g. silica or acetic acid
  • heat 80-110 °C
  • 2-aminothiophenes can be synthesized by the process described in Scheme 14.
  • Ketones (XXVIII) are converted into > -chlorovilyl aldehydes (XXXII) via a Vilsmeier-Haack-Arnold reaction upon treatment with POCI3 in DMF.
  • Subsequent reaction between > -chlorovilyl aldehydes (XXXII) and potassium thiocyanate resulted in the formation of > -thiocyanato aldehydes (XXXIII).
  • Scheme 14 synthesis of 2-aminothiophene of formula (XXIX)
  • 2-aminothiophenes (XXIX) can be synthesized by the following process described in Scheme 15.
  • -unsaturated ketones (XXXVIII) are converted to silyl enol ether (XXXIX) using triethylsilane and rhodium acetate as catalyst.
  • NBS V-bromosuccinimide
  • the present invention provides a process of manufacturing the compounds of formula (I) described herein, wherein said process is as described in any one of Schemes 1 to 15 above.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, when manufactured according to the processes disclosed herein.
  • the compounds of formula (I) and their pharmaceutically acceptable salts possess valuable pharmacological properties that make them useful for the treatment or prevention of diseases or condi ctions that are associated with the GABAA yl receptor.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use as therapeutically active substance.
  • the present invention provides a method for treating or preventing acute neurological disorders, chronic neurological disorders and/or cognitive disorders in a subject, said method comprising administering an effective amount of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, to the subject.
  • the present invention provides the use of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, in a method for treating or preventing acute neurological disorders, chronic neurological disorders and/or cognitive disorders in a subject.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, for use in a method for treating or preventing acute neurological disorders, chronic neurological disorders and/or cognitive disorders in a subject.
  • the present invention provides the use of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of prevention of acute neurological disorders, chronic neurological disorders and/or cognitive disorders.
  • said acute neurological disorders, chronic neurological disorders and/or cognitive disorders are selected from autism spectrum disorders (ASD), Angelman syndrome, age-related cognitive decline, Rett syndrome, Prader-Willi syndrome, amyotrophic lateral sclerosis (ALS), fragile-X disorder, negative and/or cognitive symptoms associated with schizophrenia, tardive dyskinesia, anxiety, social anxiety disorder (social phobia), panic disorder, agoraphobia, generalized anxiety disorder, disruptive, impulse-control and conduct disorders, Tourette’s syndrome (TS), obsessive- compulsive disorder (OCD), acute stress disorder, post-traumatic stress disorder (PTSD), attention deficit hyperactivity disorder (ADHD), sleep disorders, Parkinson’s disease (PD), Huntington’s chorea, Alzheimer’s disease (AD), mild cognitive impairment (MCI), dementia, behavioral and psychological symptoms (BPS) in neurodegenerative conditions, multi-infarct dementia, agitation, psychosis, substance-induced psychotic disorder, aggression, eating disorders, depression, chronic apathy, anhedonia, chronic fatigue, seasonal affective
  • said acute neurological disorders, chronic neurological disorders and/or cognitive disorders are selected from Alzheimer’s disease, mild cognitive impairment (MCI), age-related cognitive decline, negative and/or cognitive symptoms associated with schizophrenia, bipolar disorders, autism spectrum disorder (ASD), Angelman syndrome, Rett syndrome, Prader-Willi syndrome, epilepsy, post-traumatic stress disorder (PTSD), amyotrophic lateral sclerosis (ALS), and fragile-X disorder.
  • said acute neurological disorders, chronic neurological disorders and/or cognitive disorders are selected from autism spectrum disorder (ASD), Angelman syndrome, Alzheimer’s disease, negative and/or cognitive symptoms associated with schizophrenia and post-traumatic stress disorder (PTSD).
  • ASD autism spectrum disorder
  • Angelman syndrome Angelman syndrome
  • Alzheimer’s disease negative and/or cognitive symptoms associated with schizophrenia and post-traumatic stress disorder (PTSD).
  • PTSD post-traumatic stress disorder
  • said acute neurological disorders, chronic neurological disorders and/or cognitive disorders are selected from autism spectrum disorder (ASD), Rett syndrome, post-traumatic stress disorder and fragile-X disorder.
  • ASD autism spectrum disorder
  • Rett syndrome post-traumatic stress disorder
  • fragile-X disorder fragile-X disorder
  • said acute neurological disorders, chronic neurological disorders and/or cognitive disorders are selected from autism spectrum disorder (ASD) and Angelman syndrome.
  • said acute neurological disorders, chronic neurological disorders and/or cognitive disorders are autism spectrum disorder (ASD).
  • ASD autism spectrum disorder
  • said acute neurological disorders, chronic neurological disorders and/or cognitive disorders are Angelman syndrome.
  • said acute neurological disorders, chronic neurological disorders and/or cognitive disorders are autism spectrum disorder (ASD), targeting core symptoms and associated comorbidities, such as anxiety and irritability, social anxiety disorder (social phobia) and generalized anxiety disorder.
  • ASD autism spectrum disorder
  • the present invention provides pharmaceutical compositions comprising compounds of formula (I) or their pharmaceutically acceptable salts as defined herein and one or more pharmaceutically acceptable excipients.
  • Exemplary pharmaceutical compositions are described in the Example section below.
  • the present invention relates to pharmaceutical compositions comprising compounds of formula (I) or their pharmaceutically acceptable salts as defined above and one or more pharmaceutically acceptable excipients for the treatment or prevention of acute neurological disorders, chronic neurological disorders and/or cognitive disorders.
  • the compounds of formula (I) and their pharmaceutically acceptable salts can be used as medicaments (e.g. in the form of pharmaceutical preparations).
  • the pharmaceutical preparations can be administered internally, such as orally (e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions), nasally (e.g. in the form of nasal sprays) or rectally (e.g. in the form of suppositories).
  • the administration can also be effected parentally, such as intramuscularly or intravenously (e.g. in the form of injection solutions or infusion solutions).
  • the compounds of formula (I) and their pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic excipients for the production of tablets, coated tablets, dragees and hard gelatin capsules. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc. can be used, for example, as such excipients for tablets, dragees and hard gelatin capsules.
  • Suitable excipients for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid substances and liquid polyols, etc.
  • Suitable excipients for the production of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose, etc.
  • Suitable excipients for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc.
  • Suitable excipients for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols, etc.
  • the pharmaceutical preparations can contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
  • the dosage can vary in wide limits and will, of course, be fitted to the individual requirements in each particular case.
  • the pure enantiomers can be separated by methods described herein or by methods known to the man skilled in the art, such as e.g., chiral chromatography (e.g., chiral SFC) or crystallization.
  • Building blocks A to T can be produced according to the following synthetic procedures.
  • reaction suspension was heated to 90 °C and stirred for 40 h. After cooling, the reaction mixture was concentrated in vacuo and the residue (dark brown oil) was purified by flash column chromatography (silica, heptane / ethyl acetate 100:0 to 77:23) to obtain the title compound (1.91 g, 32 %) as a yellow solid. MS m/z: 308.1 [M+H] + , ESI pos.
  • Building block G and Building block H (7S)-9-(2,6-difluorophenyl)-3,7-dimethyl-18-thia-2,4,5,8- tetrazatetracyclo[8.8.0.02,6.011,17]octadeca-1(10),3,5,8,11(17)-pentaen-15-one (Building block G) (7S)-9-(2,6-difluorophenyl)-3,7-dimethyl-18-thia-2,4,5,8- tetrazatetracyclo[8.8.0.02,6.011,17]octadeca-1(10),3,5,8,11(17)-pentaen-14-one (Building block H) a) Mixture of (2-amino-4,5,7,8-tetrahydrospiro[cyclohepta[b]thiophene-6,2'- [1,3]dioxolan]-3-yl)(2,6-difluorophenyl)
  • reaction mixture was cooled to 0 °C, before addition of pyridine (269 mg, 0.275 mL, 3.39 mmol). After 5 min, phosphoryl chloride (135 mg, 0.0823 mL, 883 mmol) was added and the reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was poured into a stirred mixture of ethyl acetate, ice-water and saturated aqueous sodium hydrogencarbonate. After 5 min, the aqueous phase was extracted with ethyl acetate twice. The combined organic layers were washed wtih brine, dried (Na 2 SO 4 ), filtered and concentrated in vacuo.
  • the reaction mixture was allowed to warm to room temperature and stirred for 20 min. The mixture was re-cooled to 0 °C and a solution of ethyl diazoacetate in toluene (34.7 g, 304.1 mmol) was added dropwise over 15 minutes. The reaction mixture was stirred at 25 °C for 5 h, before being quenched by addition of water (50 mL). The mixture was diluted with water (300 mL) and ethyl acetate (1000 mL), then the layers were separated. The aqueous layer was further extracted with ethyl acetate (2 ⁇ 200 mL). The combined organic layers were washed with brine (60 mL), dried (Na2SO4) and concentrated in vacuo.
  • ethyl diazoacetate in toluene 34.7 g, 304.1 mmol
  • the reaction mixture was allowed to warm to room temperature and stirred for 20 min, before being re-cooled to 0 °C and ethyl bromoacetate (74.7 mL, 673.5 mmol) was added dropwise over 15 min.
  • the reaction mixture was allowed to warm to room temperature and stirred for 14 h, before being quenched by addition of water (50 mL).
  • the mixture was diluted with water (300 mL) and ethyl acetate (1000 mL), then the layers were separated.
  • the aqueous layer was further extracted with ethyl acetate (2 ⁇ 200 mL).
  • the combined organic layers were washed with brine (60 mL), dried (Na 2 SO 4 ), filtered and concentrated in vacuo.
  • reaction mixture was stirred at 0 °C for 1 h, before being quenched by saturated aqueous ammonium chloride.
  • the aqueous layer was extracted with ethyl acetate (2 ⁇ 1500 mL).
  • the combined organic layers were washed with brine (250mL), dried (Na2SO4) and concentrated in vacuo to afford the title compound (110 g, 88 %) as a yellow oil, which was used without further characterization in the next step.
  • 6-benzyloxyoxepan-3-one To a solution of dimethylsulfoxide (6.32 g, 81.0 mmol) in dichloromethane (100 mL) was added oxalyl chloride (4.69 g, 37.0 mmol) dropwise at -78 °C. After 30 min, a solution of 6-benzyloxyoxepan-3-ol (6.0 g, 27.0 mmol) in dichloromethane (50 mL) was added into the reaction mixture at -78 °C.
  • Example 1 9-(2,6-difluorophenyl)-3-methyl-18-thia-2,4,5,8- tetrazatetracyclo[8.8.0.02,6.011,17]octadeca-1(10),3,5,8,11(17)-pentaene
  • 3-(2,6-difluorophenyl)-9-thia-4,7-diazatricyclo[8.5.0.02,8]pentadeca- 1(10),2(8),3-triene-6-thione (Building block B, 75 mg, 0.207 mmol) in butan-1-ol (2 mL) was added acetohydrazide (46 mg, 0.621 mmol).
  • the reaction mixture was heated using a microwave reactor for 30 min at 100 °C, followed by 60 min at 150 °C. Then, a second portion of acetohydrazide (30 mg, 0.405 mmol) was added and the mixture was heated for further 75 min at 150 °C in the microwave reactor. The resulting yellow solution was cooled to room temperature and concentrated in vacuo. The residue was dissolved in methanol (2 mL) and purified by preparative HPLC (column Gemini NX 5u C18110A, 100 x 30 mm, 5 micron, eluent: water/acetonitrile) to afford the title compound (57 mg, 71 %) as a white powder.
  • the reaction mixture was heated using a microwave reactor for 90 min at 150 °C. Then, a second portion of acetohydrazide (390 mg, 4.74 mmol) was added and the mixture was heated for further 90 min at 150 °C in the microwave reactor. The resulting yellow solution was cooled to room temperature and concentrated in vacuo.
  • Example 4 (7S)-9-(2,6-difluorophenyl)-7-methyl-3-pyridazin-3-yl-18-thia-2,4,5,8- tetrazatetracyclo[8.8.0.02,6.011,17]octadeca-1(10),3,5,8,11(17)-pentaene a) pyridazine-3-carbohydrazide
  • a suspension of methyl pyridazine-3-carboxylate (10.0 g, 72.4 mmol) in methanol (100 mL) was heated to 60 °C, and hydrazine-monohydrate (5.44 g, 5.27 mL, 109 mmol) was added carefully.
  • Example 6 (7S)-9-(2,6-difluorophenyl)-7-methyl-18-thia-2,4,5,8- tetrazatetracyclo[8.8.0.02,6.011,17]octadeca-1(10),5,8,11(17)-tetraen-3-one a) (5S)-3-(2,6-difluorophenyl)-5-methyl-9-thia-4,7-diazatricyclo[8.5.0.02,8]pentadeca- 1(10),2(8),3-trien-6-one hydrazone To a solution of (5S)-3-(2,6-difluorophenyl)-5-methyl-9-thia-4,7-diazatricyclo[8.5.0.02,8] pentadeca-1(10),2(8),3-triene-6-thione (Building block D, 150 mg, 0.398 mmol) in 2- propanol (0.7 mL) and tetrahydrofuran (3.5
  • the reaction mixture was stirred for 4 h at 70 °C, before being cooled to room temperature.
  • the mixture was diluted with tert-butylmethyl ether (15 mL) and the organic layer was washed with aqueous sodium carbonate (1.0 M, 15 mL), water (15 mL) and brine (15 mL).
  • the aqueous layers were extracted with tert-butylmethyl ether (15 mL).
  • the combined organic layers were dried (MgSO 4 ) and concentrated in vacuo.
  • Example 7 (8S)-10-(2,6-difluorophenyl)-8-methyl-19-thia-2,6,9- triazatetracyclo[9.8.0.02,7.012,18]nonadeca-1(11),3,6,9,12(18)-pentaen-5-one a) (5S)-3-(2,6-difluorophenyl)-5-methyl-9-thia-4,7-diazatricyclo[8.5.0.02,8]pentadeca- 1(10),2(8),3-trien-6-imine A solution of (5S)-3-(2,6-difluorophenyl)-5-methyl-9-thia-4,7-diazatricyclo[8.5.0.02,8] pentadeca-1(10),2(8),3-triene-6-thione (Building block D, 112 mg, 0.297 mmol) in ammonia (7.0 M in methanol, 1.27 mL, 8.92 mmol) was stirred at 60
  • Example 8 (7S)-9-(2,6-difluorophenyl)-15,15-difluoro-3,7-dimethyl-18-thia-2,4,5,8- tetrazatetracyclo[8.8.0.02,6.011,17]octadeca-1(10),3,5,8,11(17)-pentaene
  • 5S -3-(2,6-difluorophenyl)-12,12-difluoro-5-methyl-9-thia-4,7- diazatricyclo[8.5.0.02,8]pentadeca-1(10),2(8),3-triene-6-thione
  • the reaction mixture was stirred at 70 °C for 4 h and at 23 °C for another 24 h.
  • the mixture was diluted with dichloromethane (30 mL) and washed with aqueous sodium thiosulfate (1.0 M , 10 mL).
  • the aqueous layer was extracted with dichloromethane (2 ⁇ 30 mL).
  • the combined organic layers were dried (MgSO4) and concentrated in vacuo.
  • the resulting yellow oil was purified by flash column chromatography (silica, 0-80 % ethyl acetate in heptane) to afford the title compound (221 mg, 58 %) as a white foam.
  • Example 11 (7S,16R)-9-(2,6-difluorophenyl)-16-fluoro-3,7-dimethyl-18-thia-2,4,5,8- tetrazatetracyclo[8.8.0.02,6.011,17]octadeca-1(10),3,5,8,11(17)-pentaene
  • 7S,16RS 9-(2,6-difluorophenyl)-16-fluoro-3,7-dimethyl-18-thia-2,4,5,8- tetrazatetracyclo[8.8.0.02,6.011,17]octadeca-1(10),3,5,8,11(17)-pentaene (86 mg, 0.206 mmol) was separated by chiral SFC (CHIRALPAK® IC (Daicel), 30 % methanol) to afford the enantiopure ( ⁇ )-title compound (24 mg, 27 %) as a light brown foam.
  • chiral SFC chir
  • Example 13 (7S,15RS)-9-(2,6-difluorophenyl)-3,7-dimethyl-18-thia-2,4,5,8- tetrazatetracyclo[8.8.0.02,6.011,17]octadeca-1(10),3,5,8,11(17)-pentaen-15-ol
  • 7.S 9-(2,6-difluorophenyl)-3,7-dimethyl-18-thia-2,4,5,8- tetrazatetracyclo[8.8.0.02,6.011,17]octadeca-1(10),3,5,8,11(17)-pentaen-15-one
  • Example 15 (7S,14R)-9-(2,6-difluorophenyl)-14-fluoro-3,7-dimethyl-18-thia-2,4,5,8- tetrazatetracyclo[8.8.0.02,6.011,17]octadeca-1(10),3,5,8,11(17)-pentaene
  • the enantiopure ( ⁇ )-title compound (5 mg, 4 %) was obtained as a white amorphous solid.
  • Example 16 (7S,15R)-9-(2,6-difluorophenyl)-15-fluoro-3,7-dimethyl-18-thia-2,4,5,8- tetrazatetracyclo[8.8.0.02,6.011,17]octadeca-1(10),3,5,8,11(17)-pentaene a) (7S,15RS)-9-(2,6-difluorophenyl)-3,7-dimethyl-18-thia-2,4,5,8- tetrazatetracyclo[8.8.0.02,6.011,17] octadeca-1(10),3,5,8,11(17)-pentaen-15-ol To a solution of (7S)-9-(2,6-difluorophenyl)-3,7-dimethyl-18-thia-2,4,5,8-
  • the reaction mixture was stirred at room temperature for 2 h, before being quenched by addition of water (20 mL).
  • the mixture was diluted with dichloromethane (20 mL), and aqueous phase was extracted with dichloromethane (2 ⁇ 20 mL).
  • the combined organic layers were washed with water (40 mL) and brine (40 mL), dried (Na2SO4) and concentrated in vacuo.
  • the residue was purified by chiral preparative SFC (CHIRALPAK® AS-H (Daicel), 25 % ethanol) to afford the enantiopure ( ⁇ )-title compound (64 mg, 16 %) as a white amorphous solid.
  • Example 17 (7S,15S)-9-(2,6-difluorophenyl)-15-fluoro-3,7-dimethyl-18-thia-2,4,5,8- tetrazatetracyclo[8.8.0.02,6.011,17]octadeca-1(10),3,5,8,11(17)-pentaene
  • the enantiopure ( ⁇ )-title compound (87 mg, 22 %) was obtained as a white amorphous solid.
  • Example 18 9-(2,6-difluorophenyl)-3-methyl-16-oxa-18-thia-2,4,5,8- tetrazatetracyclo[8.8.0.02,6.011,17]octadeca-1(10),3,5,8,11(17)-pentaene
  • 3-(2,6-difluorophenyl)-11-oxa-9-thia-4,7-diazatricyclo[8.5.0.02,8] pentadeca-1(10),2(8),3-trien-6-thione (Building block I, 140 mg, 0.230 mmol) in 1-butanol (4 mL) was added acethydrazide (94.9 mg, 1.15 mmol).
  • Example 21 (7S)-9-(2,6-difluorophenyl)-3,7-dimethyl-13,16-dioxa-18-thia-2,4,5,8- tetrazatetracyclo[8.8.0.02,6.011,17]octadeca-1(10),3,5,8,11(17)-pentaene
  • (13S)-15-(2,6-difluorophenyl)-13-methyl-4,7-dioxa-9-thia-11,14- diazatricyclo[8.5.0.02,8] pentadeca-1(10),2(8),14-triene-12-thione (Building block L, 590 mg, 1.55 mmol) in 1-butanol (10 mL) was added acethydrazide (638 mg, 7.75 mmol).
  • the reaction mixture was stirred with microwave irradiation at 130 °C for 60 min. A further amount of acethydrazide (638 mg, 7.75 mmol) was added and the reaction mixture was stirred in the microwave at 130 °C for another 60 min.
  • the reaction mixture was concentrated in vacuo and the residue was purified by flash column chromatography (silica, 0-6 % methanol in dichloromethane), followed by chiral SFC (Daicel CHIRALPAK® IC, 20-40 % methanol) to afford the enantiopure ( ⁇ )-title compound (74 mg, 12 %) as a light yellow solid.
  • Example 22 azetidin-1-yl-[(7S)-9-(2,6-difluorophenyl)-7-methyl-13,16-dioxa-18-thia-2,3,5,8- tetrazatetracyclo[8.8.0.02,6.011,17]octadeca-1(10),3,5,8,11(17)-pentaen-4- yl]methanone a) (13S)-11-amino-15-(2,6-difluorophenyl)-13-methyl-4,7-dioxa-9-thia-11,14- diazatricyclo[8.5.0.02,8]pentadeca-1(10),2(8),14-trien-12-one To a solution of (13S)-15-(2,6-difluorophenyl)-13-methyl-4,7-dioxa-9-thia-11,14- diazatricyclo[8.5.0.02,8]pentadeca-1(10),2(8),14
  • the mixture was stirred at 100 °C under nitrogen for 22 h, before being allowed to warm to room temperature.
  • the mixture was diluted with ethyl acetate (80 mL) and washed with water (2 ⁇ 20 mL).
  • the aqueous layer was further extracted with ethyl acetate (3 ⁇ 50 mL).
  • the combined organic layers were washed with brine (50 mL), dried (Na 2 SO 4 ) and concentrated in vacuo.
  • the residue was purified by flash column chromatography (silica, petroleum ether / ethyl acetate, 10:1 to 1:8) to afford the title compound (90 % pure, 450 mg, 44 %) as a yellow solid.
  • the reaction mixture was stirred at room temperature for 3 h, before being diluted with dichloromethane (20 mL).
  • the organic layer was washed with water (10 mL).
  • the aqueous layer was further extracted with dichloromethane (3 ⁇ 10 mL).
  • the combined organic layers were washed with brine (50 mL), dried (Na 2 SO 4 ) and concentrated in vacuo.
  • the residue was purified by flash column chromatography (silica, petroleum ether / ethyl acetate, 5:1 to 1:5), followed by chiral SFC (Chiralpak AD-H, 35 % methanol) to afford the enantiopure ( ⁇ )-title compound (19.4 mg, 36 %) as a white solid.
  • Example 24 (3-fluoroazetidin-1-yl)-[(7S)-9-(2,6-difluorophenyl)-7-methyl-13,16-dioxa-18-thia- 2,3,5,8-tetrazatetracyclo[8.8.0.02,6.011,17]octadeca-1(10),3,5,8,11(17)-pentaen-4- yl]methanone
  • the title compound was obtained in analogy to Example 22 d, using 3-fluoroazetidine instead of azetidine, as a white solid.
  • Example 25 (7S)-9-(2,6-difluorophenyl)-N-(2-fluoroethyl)-7-methyl-13,16-dioxa-18-thia-2,3,5,8- tetrazatetracyclo[8.8.0.02,6.011,17]octadeca-1(10),3,5,8,11(17)-pentaene-4- carboxamide
  • the title compound was obtained in analogy to Example 22 d, using 2-fluoroethylamine instead of azetidine, as a white solid.
  • Example 26 (8S)-10-(2,6-difluorophenyl)-4,8-dimethyl-19-thia-2,6,9- triazatetracyclo[9.8.0.02,7.012,18]nonadeca-1(11),3,6,9,12(18)-pentaen-5-one a) (5S)-3-(2,6-difluorophenyl)-5-methyl-9-thia-4,7-diazatricyclo[8.5.0.02,8]pentadeca- 1(10),2(8),3-trien-6-imine A solution of (5S)-3-(2,6-difluorophenyl)-5-methyl-9-thia-4,7-diazatricyclo[8.5.0.02,8] pentadeca-1(10),2(8),3-triene-6-thione (Building block D, 112 mg, 0.297 mmol) in ammonia (7.0 M in methanol, 1.27 mL, 8.92 mmol) was stir
  • Example 27 (7S,14R)-9-(2,6-difluorophenyl)-3,7-dimethyl-18-thia-2,4,5,8- tetrazatetracyclo[8.8.0.02,6.011,17]octadeca-1(10),3,5,8,11(17)-pentaen-14-ol
  • (7S)-9-(2,6-difluorophenyl)-3,7-dimethyl-18-thia-2,4,5,8- tetrazatetracyclo[8.8.0.02,6.011,17] octadeca-1(10),3,5,8,11(17)-pentaen-14-one (Building block H, 1.60 g, 3.88 mmol) in methanol (40 mL) was added at 0-4 °C (ice bath) lithium borohydride (253 mg, 11.6 mmol).
  • the reaction mixture was stirred at room temperature for 3 h, before being quenched by addition of ice-water (20 mL).
  • the mixture was partitioned between dichloromethane (50 mL) and semi-saturated aqueous ammonium chloride (20 mL).
  • the aqueous phase was extracted with dichloromethane (2 ⁇ 50 mL).
  • the combined organic layers were washed with water (50 mL) and brine (50 mL), dried (Na2SO4) and concentrated in vacuo.
  • Example 28 (7S)-9-(2,6-difluorophenyl)-4,7-dimethyl-13,16-dioxa-18-thia-2,3,5,8- tetrazatetracyclo[8.8.0.02,6.011,17]octadeca-1(10),3,5,8,11(17)-pentaene a) (13S)-11-amino-15-(2,6-difluorophenyl)-13-methyl-4,7-dioxa-9-thia-11,14- diazatricyclo[8.5.0.02,8]pentadeca-1(10),2(8),14-trien-12-one To a solution of (13S)-15-(2,6-difluorophenyl)-13-methyl-4,7-dioxa-9-thia-11,14- diazatricyclo[8.5.0.02,8]pentadeca-1(10),2(8),14-triene-12-one (Building block K, 1.5 g,
  • Example 29 (3-tert-butoxyazetidin-1-yl)-[(7S)-9-(2,6-difluorophenyl)-7-methyl-13,16-dioxa-18- thia-2,3,5,8-tetrazatetracyclo[8.8.0.02,6.011,17]octadeca-1(10),3,5,8,11(17)-pentaen-4- yl]methanone
  • the title compound was obtained in analogy to Example 22 d, using 3-tert-butoxyazetidine instead of azetidine, as a white solid.
  • Example 30 (7S,15S)-9-(2,6-difluorophenyl)-3,7,15-trimethyl-13,16-dioxa-18-thia-2,4,5,8- tetrazatetracyclo[8.8.0.02,6.011,17]octadeca-1(10),3,5,8,11(17)-pentaene
  • (6S,13S)-15-(2,6-difluorophenyl)-6,13-dimethyl-4,7-dioxa-9-thia- 11,14-diazatricyclo[8.5.0.02,8]pentadeca-1(10),2(8),14-trien-12-one (Building block N, 100 mg, 0.3 mmol) in anhydrous tetrahydrofuran (10 mL) was added sodium hydride (60 % dispersion in mineral oil, 21 mg, 0.5 mmol) at 0 °C.
  • Example 31 [(7S)-9-(2,6-Difluorophenyl)-7-methyl-13,16-dioxa-18-thia-2,3,5,8- tetrazatetracyclo[8.8.0.02,6.011,17]octadeca-1(10),3,5,8,11(17)-pentaen-4-yl]-(3- ethoxyazetidin-1-yl)methanone
  • the title compound was obtained in analogy to Example 22 d, using 3-ethoxyazetidine instead of azetidine, as an off-white solid.
  • Example 32 (3-Ethoxyazetidin-1-yl)-[(7S)-14,14,15,15-tetradeuterio-9-(2,6-difluorophenyl)-7- methyl-13,16-dioxa-18-thia-2,3,5,8-tetrazatetracyclo[8.8.0.02,6.011,17]octadeca- 1(10),3,5,8,11(17)-pentaen-4-yl]methanone a) (13S)-11-amino-5,5,6,6-tetradeuterio-15-(2,6-difluorophenyl)-13-methyl-4,7-dioxa-9- thia-11,14-diazatricyclo[8.5.0.02,8]pentadeca-1(10),2(8),14-trien-12-one To a solution of (13S)-5,5,6,6-tetradeuterio-15-(2,6-difluorophenyl)-13-methyl
  • Example 33 (7S)-9-(2,6-difluorophenyl)-3,7-dimethyl-12-oxa-18-thia-2,4,5,8- tetrazatetracyclo[8.8.0.02,6.011,17]octadeca-1(10),3,5,8,11(17)-pentaene
  • (13S)-15-(2,6-difluorophenyl)-13-methyl-3-oxa-9-thia-11,14- diazatricyclo[8.5.0.02,8]pentadeca-1(10),2(8),14-triene-12-thione (Building block O, 31 mg, 0.080 mmol) in n-butanol (0.8 mL) was added acethydrazide (31.3 mg, 0.401 mmol).
  • the vessel was cooled to 0 °C and (7S)-9-(2,6-difluorophenyl)-3,7-dimethyl-18-thia-2,4,5,8- tetrazatetracyclo-[8.8.0.02,6.011,17]octadeca-1(10),3,5,8,11(17),14-hexaene (200 mg, 0.50 mmol) was added.
  • the reaction mixture was allowed to warm to room temperature and stirred for 60 min. Thereafter, silver(I)-fluoride (192 mg, 1.51 mmol) was added and the reaction was stirred for further 12 h at room temperature.
  • the reaction mixture was poured into ice-water and extracted with ethyl acetate (2 ⁇ 50 mL).
  • Example 39 (7S,15S)-9-(2,6-difluorophenyl)-4,7,15-trimethyl-13,16-dioxa-18-thia-2,3,5,8- tetrazatetracyclo[8.8.0.02,6.011,17]octadeca-1(10),3,5,8,11(17)-pentaene a) (6S,13S)-11-amino-15-(2,6-difluorophenyl)-6,13-dimethyl-4,7-dioxa-9-thia-11,14- diazatricyclo[8.5.0.02,8]pentadeca-1(10),2(8),14-trien-12-one
  • the title compound was obtained in analogy to Example 28 a, using (6S,13S)-15-(2,6- difluorophenyl)-6,13-dimethyl-4,7-dioxa-9-thia-11,14-diazatricyclo[8.5.0.02,8]pent
  • Example 40 [(7S,15S)-9-(2,6-difluorophenyl)-7,15-dimethyl-13,16-dioxa-18-thia-2,3,5,8- tetrazatetracyclo[8.8.0.02,6.011,17]octadeca-1(10),3,5,8,11(17)-pentaen-4-yl]-(3- fluoroazetidin-1-yl)methanone
  • Example 43 (7S)-3-cyclopropyl-9-(2,6-difluorophenyl)-7-methyl-13,16-dioxa-18-thia-2,4,5,8- tetrazatetracyclo[8.8.0.02,6.011,17]octadeca-1(10),3,5,8,11(17)-pentaene
  • the title compound was obtained in analogy to Example 42, using cyclopropane carbohydrazide instead of propanoic acid hydrazide, as white solid.
  • Example 44 (7S)-9-(2,6-difluorophenyl)-3-isopropyl-7-methyl-13,16-dioxa-18-thia-2,4,5,8- tetrazatetracyclo[8.8.0.02,6.011,17]octadeca-1(10),3,5,8,11(17)-pentaene
  • the title compound was obtained in analogy to Example 42, using isobutyric acid hydrazide instead of propanoic acid hydrazide, as white solid.
  • Example 45 (7S)-9-(2,6-difluorophenyl)-N-(2-hydroxy-2-methyl-propyl)-7-methyl-13,16-dioxa-18- thia-2,3,5,8-tetrazatetracyclo[8.8.0.02,6.011,17]octadeca-1(10),3,5,8,11(17)-pentaene- 4-carboxamide
  • the title compound was obtained in analogy to Example 23, using (13S)-15-(2,6- difluorophenyl)-13-methyl-4,7-dioxa-9-thia-11,14-diazatricyclo[8.5.0.02,8]pentadeca- 1(10),2(8),14-triene-12-one (Building block K) instead of (13S)-5,5,6,6-tetradeuterio-15- (2,6-difluorophenyl)-13-methyl-4,7-dioxa-9-thia-11,14- diazatricyclo
  • Example 48 (7S)-3-(difluoromethyl)-9-(2,6-difluorophenyl)-7-methyl-13,16-dioxa-18-thia-2,4,5,8- tetrazatetracyclo[8.8.0.02,6.011,17]octadeca-1(10),3,5,8,11(17)-pentaene
  • the title compound was obtained in analogy to Example 42, using 2,2- difluoroacetohydrazide instead of propanoic acid hydrazide, as brown powder.
  • Example 49 (7S,15S)-9-(2,6-difluorophenyl)-4-ethyl-7,15-dimethyl-13,16-dioxa-18-thia-2,3,5,8- tetrazatetracyclo[8.8.0.02,6.011,17]octadeca-1(10),3,5,8,11(17)-pentaene
  • the title compound was obtained in analogy to Example 39 b, using ethyl propanimidate hydrochloride instead of ethyl acetimidate hydrochloride, as a light red solid.
  • Example 50 (7S)-9-(2,6-difluorophenyl)-3,7-dimethyl-13,16-dioxa-18-thia-2,5,8- triazatetracyclo[8.8.0.02,6.011,17]octadeca-1(10),3,5,8,11(17)-pentaene a) (13S)-15-(2,6-difluorophenyl)-13-methyl-4,7-dioxa-9-thia-11,14- diazatricyclo[8.5.0.02,8]pentadeca-1(10),2(8),14-trien-12-imine A solution of ammonia (7.0 M in methanol, 3.19 mL, 22.34 mmol) and (13S)-15-(2,6- difluorophenyl)-13-methyl-4,7-dioxa-9-thia-11,14-diazatricyclo[8.5.0.02,8] pentadeca- 1(10),2(8),14
  • Example 53 (7S,15S)-9-(2,6-difluorophenyl)-N-(2-hydroxyethyl)-7,15-dimethyl-13,16-dioxa-18- thia-2,3,5,8-tetrazatetracyclo[8.8.0.02,6.011,17]octadeca-1(10),3,5,8,11(17)-pentaene- 4-carboxamide a) ethyl (7S,15S)-9-(2,6-difluorophenyl)-7,15-dimethyl-13,16-dioxa-18-thia-2,3,5,8- tetrazatetracyclo[8.8.0.02,6.011,17]octadeca-1(10),3,5,8,11(17)-pentaene-4-carboxylate
  • the title compound was obtained in analogy to Example 22 a and b, using (6S,13S)-15- (2,6-difluorophenyl
  • Example 54 (7S,16R)-9-(2,6-difluorophenyl)-16-fluoro-3,7-dimethyl-13-oxa-18-thia-2,4,5,8- tetrazatetracyclo[8.8.0.02,6.011,17]octadeca-1(10),3,5,8,11(17)-pentaene a) (7S)-9-(2,6-difluorophenyl)-3,7-dimethyl-13-oxa-18-thia-2,4,5,8- tetrazatetracyclo[8.8.0.02,6.011,17]octadeca-1(10),3,5,8,11(17)-pentaen-16-one To a solution of (7S)-9-(2,6-difluorophenyl)-3,7-dimethyl-13-oxa-18-thia-2,4,5,8- tetrazatetracyclo[8.8.0.02,6.011,17]octade
  • Example 55 (7S,16S)-9-(2,6-difluorophenyl)-16-fluoro-3,7-dimethyl-13-oxa-18-thia-2,4,5,8- tetrazatetracyclo[8.8.0.02,6.011,17]octadeca-1(10),3,5,8,11(17)-pentaene
  • the enantiopure ( ⁇ )-title compound (19 mg, 15 %) as a white amorphous freeze-dried solid.
  • Example 56 (7S,14R)-9-(2,6-difluorophenyl)-14-fluoro-3,7-dimethyl-16-oxa-18-thia-2,4,5,8- tetrazatetracyclo[8.8.0.02,6.011,17]octadeca-1(10),3,5,8,11(17)-pentaene a) (7S)-14-benzyloxy-9-(2,6-difluorophenyl)-3,7-dimethyl-16-oxa-18-thia-2,4,5,8- tetrazatetracyclo[8.8.0.02,6.011,17]octadeca-1(10),3,5,8,11(17)-pentaene To a solution of (5S)-13-benzyloxy-3-(2,6-difluorophenyl)-5-methyl-11-oxa-9-thia-4,7- diazatricyclo[8.5.0.02,8]pentadeca-1(10),2
  • Example 57 (7S)-9-(2,6-difluorophenyl)-4,7-dimethyl-13-oxa-18-thia-2,3,5,8- tetrazatetracyclo[8.8.0.02,6.011,17]octadeca-1(10),3,5,8,11(17)-pentaene
  • the enantiopure ( ⁇ )-title compound was obtained in analogy to Example 39, using (5S)-3- (2,6-difluorophenyl)-5-methyl-14-oxa-9-thia-4,7-diazatricyclo[8.5.0.02,8]pentadeca- 1(10),2(8),3-trien-6-one (Building block R) instead of (6S,13S)-15-(2,6-difluorophenyl)- 6,13-dimethyl-4,7-dioxa-9-thia-11,14-diazatricyclo[8.5.0.02,8]pentadeca-1(10),
  • the suspension was stirred for 15 h, before being quenched by a slow addition of a saturated aqueous sodium hydrogen carbonate until no more gas evolution was observed.
  • the mixture was diluted with dichloromethane (20 mL) and the organic phase washed with water (3 ⁇ 10 mL), dried (Na 2 SO 4 ) and concentrated in vacuo.
  • Example 60 (7S)-9-(2,6-difluorophenyl)-N-[(1-hydroxycyclopropyl)methyl]-7-methyl-13,16-dioxa- 18-thia-2,3,5,8-tetrazatetracyclo[8.8.0.02,6.011,17]octadeca-1(10),3,5,8,11(17)- pentaene-4-carboxamide
  • the title compound was obtained in analogy to Example 53, using 1-(aminomethyl)- cyclopropanol instead of 2-hydroxyethylamine in step b), as a light yellow solid.
  • Example 61 (7S)-9-(2-chloro-6-fluoro-phenyl)-3,7-dimethyl-13-oxa-18-thia-2,4,5,8- tetrazatetracyclo[8.8.0.02,6.011,17]octadeca-1(10),3,5,8,11(17)-pentaene
  • the enantiopure ( ⁇ )-title compound was obtained in analogy to Example 52, using (5S)-3- (2-chloro-6-fluoro-phenyl)-5-methyl-14-oxa-9-thia-4,7- diazatricyclo[8.5.0.02,8]pentadeca-1(10),2(8),3-trien-6-one (Building block T) instead of (5S)-3-(2,6-difluorophenyl)-5-methyl-14-oxa-9-thia-4,7- diazatricyclo[8.5.0.02,8
  • the mixture was heated to 100 o C undernitrogen and stirred for 22 h. After cooling down to room temperature, the mixture was diluted with ethyl acetate (20 mL). The organic phase was washed with water (10 mL). The aqueous layer was further extracted with ethyl acetate (3 ⁇ 50 mL). The combined organic layers were washed with brine (50 mL), dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash column chromatography (silica, petroleum ethe r/ ethyl acetate 10:1 to 1:8) to afford the title compound (450 mg, 90 % pure) as a yellow solid.
  • Example 64 (7S)-9-(2,6-difluorophenyl)-N-(cis-3-hydroxycyclobutyl)-7-methyl-13-oxa-18-thia- 2,3,5,8-tetrazatetracyclo[8.8.0.02,6.011,17]octadeca-1(10),3,5,8,11(17)-pentaene-4- carboxamide
  • the title compound was obtained in analogy to Example 63, using cis-3- aminocyclobutanol hydrochloride instead of trans-3-aminocyclobutanol hydrochloride, as an off-white solid.
  • Example 65 (7S)-9-(2,6-difluorophenyl)-N-[(1-hydroxycyclopropyl)methyl]-7-methyl-13,16-dioxa- 18-thia-2,5,8-triazatetracyclo[8.8.0.02,6.011,17]octadeca-1(10),3,5,8,11(17)-pentaene- 4-carboxamide
  • the title compound was obtained in analogy to Example 59, using 1- (aminomethyl)cyclopropanol instead of 1-amino-2-methylpropan-2-ol in step e), as a light yellow solid.
  • Example 66 (7S)-9-(2,6-difluorophenyl)-N-(2-hydroxyethyl)-7-methyl-13-oxa-18-thia-2,5,8- triazatetracyclo[8.8.0.02,6.011,17]octadeca-1(10),3,5,8,11(17)-pentaene-4- carboxamide a) (5S)-3-(2,6-difluorophenyl)-5-methyl-14-oxa-9-thia-4,7- diazatricyclo[8.5.0.02,8]pentadeca-1(10),2(8),3-triene-6-thione A solution of (5S)-3-(2,6-difluorophenyl)-5-methyl-14-oxa-9-thia-4,7- diazatricyclo[8.5.0.02,8]pentadeca-1(10),2(8),3-trien-6-one (Building Block R, 2 g, 5.5 mmol) and pyridine
  • Example 68 (7S)-9-(2,6-difluorophenyl)-N-[(1-hydroxycyclopropyl)methyl]-7-methyl-13-oxa-18- thia-2,5,8-triazatetracyclo[8.8.0.02,6.011,17]octadeca-1(10),3,5,8,11(17)-pentaene-4- carboxamide
  • the title compound was obtained in analogy to Example 66, using 1-(aminomethyl)- cyclopropanol instead of 2-hydroxyethylamine in step f), as an off-white solid.
  • Example 70 (7S)-9-(2,6-difluorophenyl)-7-methyl-N-[(2R)-3,3,3-trifluoro-2-hydroxy-2-methyl- propyl]-13-oxa-18-thia-2,3,5,8-tetrazatetracyclo[8.8.0.02,6.011,17]octadeca- 1(10),3,5,8,11(17)-pentaene-4-carboxamide
  • the title compound was obtained in analogy to Example 22, using ethyl (7S)-9-(2,6- difluorophenyl)-7-methyl-13-oxa-18-thia-2,3,5,8- tetrazatetracyclo[8.8.0.02,6.011,17]octadeca-1(10),3,5,8,11(17)-pentaene-4-carboxylate instead of ethyl (7S)-9-(2,6
  • Example 71 (7S)-9-(2,6-difluorophenyl)-N-(2-hydroxy-2-methyl-propyl)-7-methyl-13-oxa-18-thia- 2,3,5,8-tetrazatetracyclo[8.8.0.02,6.011,17]octadeca-1(10),3,5,8,11(17)-pentaene-4- carboxamide
  • the title compound was obtained in analogy to Example 62, using 1-amino-2- methylpropan-2-ol instead of 1-(aminomethyl)-cyclopropanol in step c), as a white solid.
  • the vial was capped and heated in a microwave oven to 130 °C for 3 h.
  • the reaction mixture was concentrated in vacuo, adsorbed on ISOLUTE ® HM-N and purified by flash column chromatography (silica, 0 to 7 % methanol in dichloromethane), followed by SFC (Reprosil Chiral-NR, methanol containing 0.2 % diethyl amine) to afford the title compound (10.8 mg, 14 %) as a light brown solid.
  • MS 385.3 ([M+H] + ), ESI pos.
  • the 28 amino acid long signal peptide (Met1 to Ala28)of the human GABA A ⁇ 2 subunit was substituted by the 31 amino acid long signal peptide (Met1 to Ser31) of human GABA A ⁇ 5 subunit.
  • Harvested pellets from HEK293F cells expressing the different GABA A receptor subtypes were resuspended in Mannitol Buffer pH 7.2-7.4 (Mannitol 0.29 M, Triethylamine 10 mM, Acetic acid 10 mM, EDTA 1mM plus protease inhibitors (20 tablets Complete, Roche Diagnostics Cat.
  • the resuspended pellet was transferred into a 250ml Corning centrifugal beaker and centrifuged at 1500xg for 10 minutes at 4°C (Beckman Avanti J-HC; rotor JS-4.2). The supernatant (S1) was then transferred in the 2l Schott flask and the pellet was discarded. The supernatants (S1) were centrifuged in 500ml Beckman polypropylene centrifugal beaker at 15’000xg for 30 minutes at 4°C (Beckman Avanti J-20 XP; rotor JLA-10.500). The pellet (P2) was resuspended with Mannitol Buffer 1:1 and frozen at -80°C.
  • the supernatant (S2) was centrifuged in 100 ml Beckman polypropylene centrifugal tubes at 48000xg for 50 minutes at 4°C (Beckman Avanti J-20 XP; rotor JA-18). The supernatant (S3) was discarded and the pellet (P3) was resuspended with 1:1 Mannitol Buffer. The P2 and P3 protein concentration was determined with the BIORAD Standard assay method with bovine serum albumin as standard and measured on the NANO-Drop 1000. The membrane suspension was aliquots (500 ⁇ l per tube) and stored at -80°C until required.
  • Membrane homogenates were resuspended and polytronised (Polytron PT1200E Kinematica AG) in Potassium Phosphate 10 mM, KCl 100 mM binding buffer at pH 7.4 to a final assay concentration determined with a previous experiment.
  • Radioligand binding assays were carried out in a volume of 200 ⁇ L (96-well plates) which contained 100 ⁇ L of cell membranes, [ 3 H]RO7239181 at a concentration of 1.5 nM ( ⁇ 5 ⁇ 2 ⁇ 1) or 20-30 nM ( ⁇ 1 ⁇ 2 ⁇ 1, ⁇ 2 ⁇ 2 ⁇ 1) and the test compound in the range of [0.3- 10000] ⁇ 10 -9 M.
  • Nonspecific binding was defined by 10 ⁇ 10 -6 ( ⁇ 5 ⁇ 2 ⁇ 1) and 30 ⁇ 10 -6 M RO7239181 and typically represented less than 5% ( ⁇ 5 ⁇ 2 ⁇ 1) and less than 20% ( ⁇ 1 ⁇ 2 ⁇ 1, ⁇ 2 ⁇ 2 ⁇ 1) of the total binding.
  • Assays were incubated to equilibrium for 1 hour at 4 °C and then, membranes were filtered onto unifilter (96-well white microplate with bonded GF/C filters preincubated 20-50 minutes in 0.3% Polyethylenimine) with a Filtermate 196 harvester (Packard BioScience) and washed 4 times with cold Potassium Phosphate 10 mM pH 7.4, KCl 100 mM binding buffer.
  • Ki values were calculated using Excel-Fit (Microsoft) and are the means of two determinations.
  • the compounds of the accompanying examples were tested in the above described assays, and the preferred compounds were found to possess a Ki value for the displacement of [ 3 H]RO7239181 from GABAA ⁇ 1 subunit-containing receptors (e.g. ⁇ 5 ⁇ 2 ⁇ 1, ⁇ 2 ⁇ 2 ⁇ 1, ⁇ 1 ⁇ 2 ⁇ 1) of 100 nM or less. Most preferred are compounds with a Ki (nM) ⁇ 50.
  • Representative test results, obtained by the above described assay measuring binding affinity to HEK293 cells expressing human (h) receptors are shown in the Table 1.
  • the mixture was diluted with dichloromethane (600 mL) and washed with water (500 mL) and brine (4 ⁇ 500 mL), dried (Na 2 SO 4 ) and concentrated in vacuo.
  • the residue was purified by chromatography (silica, petroleum ether / ethyl acetate, 1:0 to 2:1).
  • the solid was suspended in petroleum ether (200 mL) and stirred at room temperature for 20 min. The suspension was filtered and the solid was dried in vacuo to afford the title compound (96.0 g, 84 %) as a yellow solid.
  • the reaction mixture was stirred at 135 °C for 36 h.
  • the reaction mixture was concentrated in vacuo to remove pyridine.
  • the residue was diluted with ethyl acetate (2000 mL) and washed with aqueous HCl (1.0 M, 3 ⁇ 1500 mL), water (2000 mL) and brine (2 ⁇ 1000 mL), dried (Na2SO4), filtered and concentrated in vacuo.
  • the crude product was purified by flash column chromatography (silica, petroleum ether / ethyl acetate 10:1 to 2:1) to afford the title compound (10.1 g, 12 %) as an off-white solid.
  • compounds with a Ki ⁇ 1 ⁇ 3 ⁇ 2 (nM) > 300 are binding selectively for the ⁇ 1 subunit- containing GABA A receptors relative to ⁇ 2 subunit-containing GABA A receptors.
  • compounds of the present invention have ⁇ 2/ ⁇ 1 selectivity ratio defined as “Ki ⁇ 1 ⁇ 3 ⁇ 2 (nM) / K i ⁇ 2 ⁇ 2 ⁇ 1 (nM)” above 10-fold, or LogSel defined as “Log[K i ⁇ 1 ⁇ 3 ⁇ 2 (nM) / K i ⁇ 2 ⁇ 2 ⁇ 1 (nM)]” above 1.
  • Table 1 Functional expression of GABAA receptors: Xenopus oocytes preparation Xenopus laevis oocytes at maturation stages V-VI were used for the expression of cloned mRNA encoding GABA A receptor subunits.
  • Xenopus oocytes microinjection Oocytes were plated in 96-well plates for microinjection using the Roboinject automated instrument (MultiChannelSystems, Reutlingen, Germany).
  • RNA concentrations ranged between 20 and 200 pg/ ⁇ L/subunit and were adjusted in pilot experiments to obtain GABA responses of a suitable size and a maximal effect of Flunitrazepam, Triazolam and Midazolam, reference benzodiazepine positive allosteric modulators (PAM) at the GABAA receptor benzodiazepine (BZD) binding site.
  • PAM benzodiazepine positive allosteric modulators
  • Electrophysiology Electrophysiological experiments were performed using the Roboocyte instrument (MultiChannelSystems, Reutlingen, Germany) on days 3 to 5 after the micro-injection of mRNA. During the experiment the oocytes were constantly superfused by a solution containing (in mM) NaCl 90, KCl 1, HEPES 5, MgCl21, CaCl21 (pH 7.4).
  • Oocytes were impaled by two glass microelectrodes (resistance: 0.5-0.8 M ⁇ ) which were filled with a solution containing KCl 1M + K-acetate 1.5 M and voltage-clamped to -80 mV.
  • the recordings were performed at room temperature using the Roboocyte two-electrode voltage clamp system (Multichannelsystem). After an initial equilibration period of 1.5 min GABA was added for 1.5 min at a concentration evoking approximately 20% of a maximal current response (EC 20 ).
  • Tablets comprising compounds of formula (I) are manufactured as follows:
  • Manufacturing Procedure 1 Mix ingredients 1, 2, 3 and 4 and granulate with purified water.
  • Capsules comprising compounds of formula (I) are manufactured as follows:
  • a compound of formula I lactose and com starch are firstly mixed in a mixer and then in a comminuting machine. The mixture is returned to the mixer; the talc is added thereto and mixed thoapproximatively. The mixture is filled by machine into suitable capsules, e.g. hard gelatin capsules.
  • Injection solutions comprising compounds of formula (I) are manufactured as follows:

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Abstract

L'invention concerne de nouveaux composés hétérocycliques ayant la formule générale (I), et des sels pharmaceutiquement acceptables de ceux-ci, les variables étant telles que décrites dans la description. L'invention concerne en outre des compositions pharmaceutiques comprenant les composés, des procédés de fabrication des composés et des procédés d'utilisation des composés en tant que médicaments, en particulier des procédés d'utilisation des composés pour le traitement ou la prévention de troubles neurologiques aigus, de troubles neurologiques chroniques et/ou de troubles cognitifs.
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Citations (2)

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US4621083A (en) 1984-10-01 1986-11-04 Boehringer Ingelheim Kg PAF-antagonistic diazepines

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DE2533924A1 (de) * 1975-07-30 1977-02-17 Boehringer Sohn Ingelheim Verfahren zur herstellung von substituierten 6-aryl-4h-s-triazolo- eckige klammer auf 3,4-c eckige klammer zu -thieno- eckige klammer auf 2,3-e eckige klammer zu -1,4-diazepinen
US4621083A (en) 1984-10-01 1986-11-04 Boehringer Ingelheim Kg PAF-antagonistic diazepines

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RICHARD C. LAROCK: "Comprehensive Organic Transformations: A Guide to Functional Group Preparations", 2018, JOHN WILEY & SONS
SVETLOV STANISLAV I. ET AL: "The specific binding of the platelet-activating factor (PAF) receptor antagonist WEB 2086 and the benzodiazepine flunitrazepam to rat hepatocytes", LIFE SCIENCE, vol. 58, no. 5, 1 December 1995 (1995-12-01), GB, pages PL81 - PL86, XP055918289, ISSN: 0024-3205, DOI: 10.1016/0024-3205(95)02302-X *
WATERS LAURA ET AL: "The use of a quantitative structure-activity relationship (QSAR) model to predict GABA-A receptor binding of newly emerging benzodiazepines", vol. 58, no. 3, 1 May 2018 (2018-05-01), GB, pages 219 - 225, XP055918334, ISSN: 1355-0306, Retrieved from the Internet <URL:https://www.sciencedirect.com/science/article/pii/S1355030617301545/pdfft?md5=a39ad079f8c8ec3d1b69c117c0e7040e&pid=1-s2.0-S1355030617301545-main.pdf> DOI: 10.1016/j.scijus.2017.12.004 *

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